Lasmiditan

Because of the potential of lasmiditan to cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions, lasmiditan should be used with caution if used in combination with alcohol or other CNS depressants.

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). In a drug interaction study, lasmiditan increased the systemic exposure of coadministered dabigatran (P-gp substrate) by approximately 25%. Therefore, when lasmiditan is administered with P-gp substrates that have a narrow therapeutic index (such as digoxin), increases in the systemic exposure of the coadministered medication may be clinically meaningful. In the same study, no significant change in rosuvastatin (BCRP substrate) PK was observed when it was coadministered with lasmiditan.

The use of lasmiditan has not been studied in subjects with severe hepatic impairment and therefore is not recommended for this population.

Concomitant administration of lasmiditan and medicinal products (e.g., SSRIs, SNRIs, TCAs) that increase serotonin may increase the risk of serotonin syndrome. Clinical experience for the use of lasmiditan and triptans in temporal proximity is limited. The risks of developing serotonin syndrome may be additive. Caution is advised.

Lasmiditan has been associated with a lowering of heart rate (HR). Propranolol and lasmiditan together decreased HR by a mean maximum of 19.3 beats per minute (bpm), i.e., an additional lowering of 5.1 bpm compared to propranolol alone. This should be taken into consideration for patients in whom these magnitudes of HR decrease may pose a concern, including patients taking medicinal products that lower heart rate.

There is a limited amount of data from the use of lasmiditan in pregnant women. Studies in animals have shown reproductive toxicity. The effects of lasmiditan on human foetal development are not known. Lasmiditan is not recommended during pregnancy.

Lasmiditan and/or its metabolites were excreted into the milk of lactating rats. There are no data on the presence of lasmiditan in human milk, the effects of lasmiditan on the breastfed infant, or the effects of lasmiditan on milk production.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from lasmiditan therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Exposure of the newborn can be minimised by avoiding breast-feeding for 24 hours after treatment.

Fertility

It is unknown whether lasmiditan affects human reproductive potential. Animal studies do not indicate any effect on fertility.

Lasmiditan has major influence on the ability to drive and use machines. Driving performance was evaluated using a computer-based driving simulation. The primary outcome measure was the difference from placebo in the Standard Deviation of Lateral Position (SDLP), a measure of driving performance. Administration of single 50 mg, 100 mg, or 200 mg doses of lasmiditan significantly impaired subjects' ability to drive 90 minutes after dosing. In another study of lasmiditan 100 mg or 200 mg, driving performance did not reach the threshold for driving impairment at 8 hours or later after administration of lasmiditan at either dose.

Patients should be advised not to engage in activities requiring heightened attention, such as operating machinery or driving, for at least 8 hours after taking each dose of lasmiditan, even if they feel well enough to do so. Patients who cannot follow this advice should not take lasmiditan.

Summary of the safety profile

The most commonly occurring adverse reactions are dizziness (19.9%), somnolence (7.8%), fatigue (7.7%), paraesthesia (6.8%), nausea (4.9%), vertigo (2.6%), hypoaesthesia (2.5%), and muscular weakness (2.3%). Most of the adverse events showed a dose response.

Tabulated list of adverse reactions

In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency gradings are: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000).

Adverse reactions:

Description of selected adverse reactions

Heart rate decrease

In clinical pharmacology studies, lasmiditan was associated with decreases in heart rate of 5 to 10 bpm compared to a decrease of 2-5 bpm for placebo. Incidence of bradycardia (<50 bpm and a decrease from baseline ≥15 bpm) observed in lasmiditan-treated subjects was 7% for 50 mg, 3% for 100 mg, 4% for 200 mg, and 1% for placebo.

Blood pressure increase

Single dose administration of lasmiditan may lead to a transient increase in blood pressure. In non-elderly healthy volunteers a mean increase from baseline in ambulatory systolic and diastolic blood pressure of approximately 2 to 3 mm Hg one hour after administration of 200 mg lasmiditan was observed, compared to an increase of about 1 mm Hg for placebo. In healthy volunteers over 65 years of age, the mean increase from baseline in ambulatory systolic blood pressure was 7 mm Hg one hour after administration of 200 mg lasmiditan compared to a mean increase of 4 mm Hg for placebo. By 2 hours, there were no increases in mean blood pressure with lasmiditan compared to placebo. Clinical data for the use of lasmiditan in patients with ischemic heart disease is limited.

Hypersensitivity

Events of hypersensitivity, including angioedema, rash, and photosensitivity reaction, occurred in patients treated with lasmiditan. In clinical trials, hypersensitivity was reported in 0.1% of patients treated with lasmiditan compared to no patients in the placebo group; all events were mild to moderate in severity and occurred within minutes to a day after dosing with lasmiditan. If a serious or severe hypersensitivity reaction occurs, appropriate therapy should be initiated and administration of lasmiditan should be discontinued.

Dizziness

In clinical trials, dizziness was the most common adverse reaction, reported in 19.9% of patients. It was generally mild to moderate in severity (severe dizziness 1.2%) and self-limiting with a median time to onset of 0.7 hours and a median duration of 2 hours. No accidents or injuries were reported in patients reporting dizziness. The frequency of patients reporting dizziness, and other common adverse events, typically decreases with repeat dosing.